CN104337811A - Repaglinide-metformin hydrochloride tablet and preparing method thereof - Google Patents
Repaglinide-metformin hydrochloride tablet and preparing method thereof Download PDFInfo
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- CN104337811A CN104337811A CN201310336643.9A CN201310336643A CN104337811A CN 104337811 A CN104337811 A CN 104337811A CN 201310336643 A CN201310336643 A CN 201310336643A CN 104337811 A CN104337811 A CN 104337811A
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Abstract
The invention discloses a prescription of a repaglinide-metformin hydrochloride tablet and a preparation technology thereof. In particular, a solid dispersion water solution technology is used; the problem that repaglinide is insoluble in water can be solved only through common wet granulations; dissolved objects and related matter are both superior to those of foreign objects. Microcrystalline celluloses and sorbitol serve as fillers; polyvinylpolypyrrolidone serves as disintegrating agents; PVPk30 serves as bonding agents; silicon dioxide serves as lubricating agents; meglumine serves as saltiness agents; and poloxamer 188 serves as solubilizers. The repaglinide-metformin hydrochloride tablet prepared with the technology is fewer in use auxiliary material; the high dissolving performance and the high stability can be kept; the preparation technology is simple; the technology cost is lower; and the repaglinide-metformin hydrochloride tablet is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical field, particularly relate to a kind of Repaglinide-metformin hydrochloride tablet recipe and preparation process thereof, belong to medical art.
Background technology
The endocrine metabolism disease of diabetes to be a kind of with hyperglycemia be feature, usually causes human body various tissue, particularly eyes, kidney, nerve, the damage of heart and blood vessel, functional defect and exhaustion.Along with the raising of people's living standard, the sickness rate of diabetes is also in comprehensive ascendant trend.At present, the pathogenesis of diabetes is also not fully aware of, but two classes can be divided into according to the Pathologic Characteristics that patient demonstrates: type i diabetes, namely insulin-dependent (IDDM) must rely on exogenous insulin to the activity of supporting the family, type ii diabetes, i.e. non-insulin-depending type (NIDDM), this kind of diabetics need not rely on exogenous insulin, mostly be adult, be mostly overweight people.Type ii diabetes patient accounts for more than 80% greatly.
Repaglinide is a kind of non-sulfonylurea Drugs Promoting Insulin Secretion, the 36KDA protein-specific of this product on the potassium-channel of the outer dependency ATP of islet cells film is combined, potassium channel is closed, calcium channel is open, flow of calcium ions, promotes insulin secretion, its effect is faster than sulfonylurea, the blood glucose and the sugar that reduce type ii diabetes patient close hemoglobin level, can not accumulate in the tissue, have good safety.Metformin hydrochloride does not directly stimulate the insulin secretion of B cell, but by suppressing intestinal to absorption, the hepatocellular gluconeogenesis of glucose and improving body to insulin sensitivity, increase the peripheral tissues such as fat, muscle to the picked-up of glucose and utilization, obviously can reduce empty stomach and post-prandial glycemia and can not hypoglycemia be caused.Because repaglinide and metformin hydrochloride have synergism and mechanism of action is complementary in blood sugar lowering.
Although had Repaglinide-metformin hydrochloride ordinary tablet to go on the market abroad, preparation process is too loaded down with trivial details, and adjunct ingredient is too many, and preparation cost is higher.
Summary of the invention
First technical problem to be solved by this invention is, provides a kind of adjuvant less but still can keep higher dissolving out capability and higher stability Repaglinide-metformin hydrochloride sheet
Second technical problem to be solved by this invention is, provides above-mentioned Repaglinide-metformin hydrochloride sheet preparation technology simple, the preparation process that process costs is lower.
In order to solve the problem, the invention provides a kind of Repaglinide-metformin hydrochloride sheet, it is characterized in that, every 10000 Repaglinide-metformin hydrochloride sheets contain:
500mg/2mg specification
500mg/1mg specification
As a preferred version, every 10000 Repaglinide-metformin hydrochloride sheets, is characterized in that, every 10000 Repaglinide-metformin hydrochloride sheets contain: 500mg/2mg specification
As a preferred version, every 10000 Repaglinide-metformin hydrochloride sheets, is characterized in that, every 10000 Repaglinide-metformin hydrochloride sheets contain: 500mg/1mg specification
2. the preparation process of Repaglinide-metformin hydrochloride sheet, comprises the following steps:
(1) take above-mentioned substance by recipe quantity, described recipe quantity refers to material and content described in claim 1 or 2 or 3;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture that step poly-(2) obtains is mixed homogeneously with metformin hydrochloride by equal increments method, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity, PLURONICS F87, PVPk30 to be dissolved in 60 DEG C of purified water and to stir;
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG;
(11) bag gastric solubility film-coat, weightening finish about 3%;
(12) high-density polyethylene bottle packaging;
The invention has the advantages that, use adjuvant less in compound Repaglinide-metformin hydrochloride slice prescription disclosed by the invention, preparation process is simple, especially solid dispersion aqueous solution technology is used, preparation process is simple, as long as with common wet granulation, namely solve the water-fast problem of repaglinide and stripping and related substance are all better than external product.Use microcrystalline Cellulose and sorbitol as filler, polyvinylpolypyrrolidone makes disintegrating agent, and PVPk30 makes binding agent, and silicon dioxide makes lubricant, and meglumine does saltiness agent, and PLURONICS F87 is as solubilizing agent.
Detailed description of the invention
Below the detailed description of the invention of the preparation process of compound Repaglinide-metformin hydrochloride sheet provided by the invention is elaborated.
The detection of compound Repaglinide-metformin hydrochloride sheet is according to (with reference to State Food and Drug Administration import drugs registered standard JX20110021)
This product is containing repaglinide (C
27h
36n
2o
4) and metformin hydrochloride (C
4h
11n
5hCl) all should be 95.0% ~ 105.0% of labelled amount.
In the chromatogram that [discriminating] (1) is recorded under assay item, the retention time of need testing solution main peak should be consistent with the retention time of repaglinide reference substance solution main peak.
(2), in the chromatogram recorded under assay item, the retention time of need testing solution main peak should be consistent with the retention time of metformin hydrochloride reference substance solution main peak.
[inspection] uniformity of dosage units gets this product 1, put in 25ml measuring bottle, add solvent (note 1) appropriate and add magnetic stirring, magnetic agitation 1 hour, taking-up magnetic stirring, and rinse with solvent (note 1), merge in flushing liquor to same measuring bottle, be diluted to scale with solvent (note 1), shake up, leave standstill to supernatant and clarify, get supernatant to filter, get subsequent filtrate as need testing solution, measure the content of repaglinide according to the method under assay item, should conform with the regulations (Chinese Pharmacopoeia version in 2010 two annex X E).
Dissolution gets this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex X C second methods), with citric acid phosphate buffer (pH5.0) [note 2] 900ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, when 15 minutes, get solution appropriate, filter, get subsequent filtrate and carry out following mensuration respectively.
Repaglinide measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With phosphate buffer
(pH2.3) [note 3]-acetonitrile-methanol (40: 49: 11) are mobile phase; Column temperature is 40 DEG C; Flow velocity is 1.0ml/min; Adopt fluorescence detector, excitation wavelength is 244nm; Emission wavelength is 348nm.Repeat sampling system employment and suitability test (E & ST) solution 5 times, the retention time at repaglinide peak must not be less than 1.5min; The relative standard deviation of repaglinide peak area must not cross 2.0%; Tailing factor should be 0.8 ~ 1.5.
Algoscopy takes repaglinide reference substance and is about 22mg, accurately weighed, puts in 100ml measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, in contrast product solution A.Precision measures reference substance solution A5ml, puts in 100ml measuring bottle, adds methanol dilution to scale, shakes up, in contrast product solution B.Precision measures reference substance solution B3ml, 20ml, 22ml and puts in 100ml, 200ml, 100ml measuring bottle respectively, add methanol 20ml, 40ml, 10ml respectively, add dissolution medium again to about 80% of measuring bottle volume, let cool to room temperature, add stripping medium again to scale, shake up, be namely mixed with concentration and be respectively 0.33 μ g/ml, 1.1 μ g/ml, 2.42 μ g/ml repaglinide standard curve solution.Using the solution of standard curve intermediate concentration as system suitability solution.Precision measures each 20 μ l of repaglinide standard curve solution respectively, and injection liquid chromatography, maps to concentration with peak area, and calculate regression equation, the correlation coefficient of repaglinide standard curve should be greater than 0.999.Get subsequent filtrate as need testing solution, precision measures need testing solution 20 μ l, injection liquid chromatography, and record chromatogram, calculates the stripping quantity of repaglinide in every sheet.Limit is 80% of labelled amount, should conform with the regulations.
Metformin hydrochloride gets subsequent filtrate 2ml, puts in 100ml measuring bottle, is diluted with water to scale, shake up, and according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IVA), measures absorbance at the wavelength place of 233nm; Separately get metformin hydrochloride reference substance 50mg, accurately weighed, put in 100ml measuring bottle, add dissolution medium and make metformin hydrochloride dissolve and be diluted to scale in right amount, shake up; Precision measures 2ml, puts in 100ml measuring bottle, is diluted with water to scale, shake up, be measured in the same method, and calculates the stripping quantity of metformin hydrochloride in every sheet.Limit is 80% of labelled amount, should conform with the regulations.
Repaglinide related substance measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability octyl silane group silica gel are filler; With phosphate buffer
(pH3.2) [note 4] is mobile phase A, with phosphate buffer (pH3.2)-acetonitrile (30: 70) for Mobile phase B; Column temperature is 40 DEG C; Flow velocity is 1.5ml/min, and according to the form below carries out linear gradient elution; Use fluorescence detector, excitation wavelength is 244nm; Emission wavelength is 348nm.
Separately get repaglinide reference substance 50mg, accurately weighed, put in 50ml measuring bottle, add methanol and make dissolving in right amount and be diluted to scale, shake up, as repaglinide reference substance stock solution; Get impurity II, impurity IV and each 6mg of impurity VI respectively, accurately weighed, put respectively in 100ml measuring bottle, add appropriate amount of ethanol and make dissolving and be diluted to scale, shake up; As each impurity reference substance stock solution; Precision measures repaglinide reference substance stock solution 2ml and each 0.1ml of above-mentioned each impurity reference substance stock solution respectively, puts in same 200ml measuring bottle, is diluted to scale, shakes up, as system suitability solution with solvent (note 1); Precision measures system suitability solution 1ml, puts in 1000ml measuring bottle, is diluted to scale, as sensitivity test solution with solvent (note 1).Get system suitability solution 50 μ l, injection liquid chromatography, record chromatogram, the retention time at repaglinide peak should between 15 ~ 23 minutes; Each peak-to-peak separating degree should meet the requirements; Repeat sample introduction sensitivity test solution 3 times, the relative standard deviation of repaglinide peak area must not cross 10%.
Algoscopy gets this product 10, puts in 100ml measuring bottle, and it is appropriate and add magnetic stirring to add solvent (note 1), magnetic agitation 1 hour, takes out magnetic stirring, and rinses with solvent (note 1), merge in flushing liquor to same measuring bottle, be diluted to scale with solvent (note 1), shake up, leave standstill to the aobvious clarification of supernatant, get supernatant and filter, get subsequent filtrate 1ml, put in 10ml measuring bottle, be diluted to scale with solvent (note 1), shake up, as need testing solution.Precision measures need testing solution 50 μ l, injection liquid chromatography, record chromatogram.Solvent peak and blank auxiliary peak (see accompanying drawing 2) is deducted in need testing solution chromatogram, as aobvious impurity peaks, by following formula with calculated by peak area, impurity II, impurity IV and impurity VI must not cross 0.2%, other single impurity must not cross 0.2%, and total impurities must not cross 0.5%.
Impurity content (%)=impurity chromatographic peak area/(repaglinide chromatographic peak area * RRF) * 100%
Metformin hydrochloride related substance need testing solution is with the need testing solution under assay item.Except determined wavelength is, other are according to the chromatographic condition under assay item, and precision measures need testing solution 20 μ l, injection liquid chromatography, record chromatogram.As aobvious impurity peaks in need testing solution chromatogram, by following formula with calculated by peak area, impurity A must not cross 0.02%, and impurity B, impurity C, impurity D and impurity E must not cross 0.1%, and other single impurity must not cross 0.1%, and total impurities must not cross 0.6%.
Impurity content (%)=impurity chromatographic peak area/(metformin hydrochloride chromatographic peak area * RRF) * 100%
Loss on drying gets this product 10, porphyrize, and it is appropriate that precision takes fine powder, and in 105 DEG C of dryings 3 hours, less loss weight must not cross 2.5% (Chinese Pharmacopoeia version in 2010 two annex VIII L).Other every rule relevant under should meeting tablet item (Chinese Pharmacopoeia version in 2010 two annex I A).
[assay] repaglinide measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).Chromatographic condition and system suitability octyl silane group silica gel are filler; With phosphate buffer (pH3.2) [note 4]-acetonitrile (44: 56) for mobile phase; Column temperature is 40 DEG C; Flow velocity is 1.0ml/min; Determined wavelength is that 245nm repeats sampling system suitability solution 5 times, and the relative standard deviation of repaglinide peak area should cross 2.0%.
It is appropriate that algoscopy gets repaglinide reference substance, accurately weighed, be solvent with mobile phase, prepare a series of repaglinide standard curve solution (at least should prepare three concentration), concentration model dimension is in 32 ~ 128 μ g/ml, using the solution of standard curve intermediate concentration as system suitability solution, precision measures each 50 μ l of repaglinide standard curve solution, injection liquid chromatography respectively, with peak area, concentration is mapped, calculate regression equation, the correlation coefficient of repaglinide standard curve should be greater than 0.999.Get this product 8, put in 100ml measuring bottle, it is appropriate to add solvent, add magnetic stirring, magnetic agitation 1 hour, take out magnetic stirring, and rinse with solvent (note 1), merge in flushing liquor to same measuring bottle, be diluted to scale with solvent (note 1), shake up, leave standstill to the aobvious clarification of supernatant, get supernatant and filter, get subsequent filtrate as need testing solution, precision measures need testing solution 50 μ l, injection liquid chromatography, record chromatogram, calculates the content of repaglinide in every sheet.
Metformin hydrochloride measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability sulfonic group cation exchange bonded silica gel are filler (as: Capcell Pak5 μ SCX UG80A, 4.6 × 150mm or other equal chromatographic columns); With the ammonium dihydrogen phosphate of 0.35mol/L (by phosphoric acid adjust ph for 3.0) for mobile phase; Column temperature is 40 DEG C; Flow velocity is 1.0ml/min; Determined wavelength is 230nm.Get metformin hydrochloride impurity A, impurity B, impurity C, impurity D and each 5.0mg of impurity E, accurately weighed, put in 100ml measuring bottle respectively, adding mobile phase makes each impurity of metformin hydrochloride all dissolve and be diluted to scale in right amount, shakes up, and precision measures each 0.5ml of above-mentioned dirt solution and metformin hydrochloride reference substance stock solution 5ml, put in same 100ml measuring bottle, be diluted to scale with mobile phase, shake up, as system suitability solution; Precision measures system suitability solution 0.5ml, puts in 1000ml measuring bottle, is diluted to scale with mobile phase, shake up, as sensitivity test solution; Get system suitability solution 20 μ l, injecting chromatograph, record chromatogram (system suitability chromatogram is shown in Fig. 3), the retention time at metformin hydrochloride peak should between 5.8 ~ 7.5 minutes; Each peak-to-peak separating degree should meet the requirements; Repeat sample introduction sensitivity test solution 3 times, the relative standard deviation of metformin hydrochloride peak area should cross 10%.Repeat sample introduction metformin hydrochloride intermediate concentration reference substance solution 5 times, the relative standard deviation of metformin hydrochloride peak area should cross 1.5%.
Algoscopy gets metformin hydrochloride reference substance 250mg, accurately weighed, puts in 50ml measuring bottle, adds mobile phase and makes dissolving in right amount and be diluted with water to scale, shake up, as metformin hydrochloride reference substance stock solution; Get metformin hydrochloride reference substance stock solution appropriate, prepare the standard curve solution (at least should prepare three concentration) of a series of metformin hydrochloride at the concentration Fan Weinei of 125 ~ 375 μ g/ml with mobile phase, precision measures each 20 μ l of metformin hydrochloride standard curve solution respectively, injection liquid chromatography, with concentration, peak area is mapped, calculate regression equation, the correlation coefficient of metformin hydrochloride standard curve should be greater than 0.999.Get this product 10, put in 1000ml measuring bottle, add mobile phase in right amount, add magnetic stirring, magnetic agitation 1 hour.Be diluted to scale with mobile phase, shake up, leave standstill to the aobvious clarification of supernatant, get supernatant and filter, get subsequent filtrate 5ml, put in the measuring bottle of 100ml, be diluted to scale with mobile phase, shake up, be need testing solution.Precision measures need testing solution 20 μ l, injection liquid chromatography, calculates the content of metformin hydrochloride in test sample, to obtain final product.
[note 1]: solvent: alcohol-water (1: 1)
[note 2]: citric acid/phosphate buffer (pH5.0): take citric acid 10.3g and disodium phosphate dihydrate 18.16g, the 950ml that adds water makes dissolving, is diluted with water to 1000ml.
[note 3]: phosphate buffer (pH2.3): take potassium dihydrogen phosphate 1.5g, adds 950ml water and makes dissolving, by phosphoric acid adjust ph to 2.3, be diluted with water to 1000ml.
[note 4]: phosphate buffer (pH3.2): take potassium dihydrogen phosphate 4g, adds the water of 950ml, by phosphoric acid adjust ph to 3.2, is diluted with water to 1000ml.
The screening of embodiment 1, Repaglinide-metformin hydrochloride tablet recipe
In early stage trial-manufacturing process, once considered that raw material mixed rear wet granulation with adjuvant, because dissolution does not reach requirement, often groped afterwards, now repaglinide is added with the form of the binding agent of solid dispersion aqueous solution together with meglumine, PLURONICS F87 and a small amount of PVPk30, its dissolution can reach more than 98%, and related substance is completely qualified.
The selection of packaging material
Repaglinide-metformin hydrochloride sheet is all very responsive for the environment of illumination, high temperature, high humidity, therefore when the selection of interior packaging material, and the coloured blister package of single aluminum.The great advantage of blister package is easy to carry, can reduce medicine and carry and taking the pollution caused in process, and blister package also has very large advantage in body constitution phase etc. of barrier properties for gases, poisture-penetrability, wholesomeness, production efficiency, dosage accuracy and prolongation medicine.
One of embodiment 2, Repaglinide-metformin hydrochloride tablet preparation technique
Every 10000 specification 500mg/2mg Repaglinide-metformin hydrochloride sheets contain:
The preparation method of the Repaglinide-metformin hydrochloride sheet described in the present embodiment, comprises following steps:
(1) metformin hydrochloride 5000g is taken, microcrystalline Cellulose 620g, sorbitol 100g, PVPk30 200g, polyvinylpolypyrrolidone 280g, repaglinide 20g, PLURONICS F87 40g, meglumine 20g, PVPk305g, silicon dioxide 35g;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture classification that step poly-(2) obtains is diffused in metformin hydrochloride, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity, PLURONICS F87, PVPk30 to be dissolved in 60 DEG C of purified water and to stir; Adding repaglinide stirring after dissolving completely makes it dissolve completely:
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and V-Mixer mixes 20 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG
(11) bag gastric solubility film-coat, weightening finish about 3%; ;
(12) high-density polyethylene bottle packaging;
Every 10000 specification 500mg/1mg Repaglinide-metformin hydrochloride sheets contain:
The preparation method of the Repaglinide-metformin hydrochloride sheet described in the present embodiment, comprises following steps:
(1) metformin hydrochloride 5000g is taken, microcrystalline Cellulose 620g, sorbitol 100g, PVPk30 200g, polyvinylpolypyrrolidone 280g, repaglinide 10g, PLURONICS F87 40g, meglumine 20g, PVPk305g, silicon dioxide 35g;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture classification that step poly-(2) obtains is diffused in metformin hydrochloride, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity, PLURONICS F87, PVPk30 to be dissolved in 60 DEG C of purified water and to stir; Adding repaglinide stirring after dissolving completely makes it dissolve completely:
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG
(11) bag gastric solubility film-coat, weightening finish about 3%; ;
(12) high-density polyethylene bottle packaging;
The Repaglinide-metformin hydrochloride sheet prepared above is carried out mass property with listing sample test difficulty of having a competition, by high performance liquid chromatography, comparative study is carried out to content, content even amount, dissolution and related substance, the results are shown in following table
Mass property main project comparative study result
The above results shows, and the independently developed product indices of my company is all better than the sample that goes on the market, and makes patient medication safer clinically.
Embodiment 3, Repaglinide-metformin hydrochloride tablet preparation technique two
Every 10000 specification 500mg/2mg compound Repaglinide-metformin hydrochloride sheets contain:
The preparation method of the Repaglinide-metformin hydrochloride sheet described in the present embodiment, comprises following steps:
(1) metformin hydrochloride 5000g is taken, microcrystalline Cellulose 620g, sorbitol 100g, PVPk30 200g, polyvinylpolypyrrolidone 280g, repaglinide 20g, PLURONICS F87 40g, meglumine 20g, PVPk305g, silicon dioxide 35g;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture that step poly-(2) obtains is mixed homogeneously with metformin hydrochloride by equal increments method, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity to be dissolved in purified water and stir dissolve completely after add repaglinide and stir and make it dissolve completely.PLURONICS F87, PVPk30 are dissolved in another part 60 DEG C of purified water also stirring and make it dissolve completely:
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG
(11) bag gastric solubility film-coat, weightening finish about 3%;
(12) high-density polyethylene bottle packaging;
Every 10000 specification 500mg/1mg Repaglinide-metformin hydrochloride sheets contain:
The preparation method of the Repaglinide-metformin hydrochloride sheet described in the present embodiment, comprises following steps:
(1) metformin hydrochloride 5000g is taken, microcrystalline Cellulose 620g, sorbitol 100g, PVPk30 200g, polyvinylpolypyrrolidone 280g, repaglinide 10g, PLURONICS F87 40g, meglumine 20g, PVPk305g, silicon dioxide 35g;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture that step poly-(2) obtains is mixed homogeneously with metformin hydrochloride by equal increments method, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity to be dissolved in purified water and stir dissolve completely after add repaglinide and stir and make it dissolve completely.PLURONICS F87, PVPk30 are dissolved in another part 60 DEG C of purified water also stirring and make it dissolve completely:
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG
(11) bag gastric solubility film-coat, weightening finish about 3%; ;
(12) high-density polyethylene bottle packaging;
Embodiment 3, Repaglinide-metformin hydrochloride tablet preparation technique three
Every 10000 specification 500mg/2mg compound Repaglinide-metformin hydrochloride sheets contain:
The preparation method of the Repaglinide-metformin hydrochloride sheet described in the present embodiment, comprises following steps:
(1) metformin hydrochloride 5000g is taken, microcrystalline Cellulose 680g, sorbitol 100g, PVPk30 200g, polyvinylpolypyrrolidone 280g, repaglinide 20g, PLURONICS F87 40g, meglumine 20g, PVPk305g, silicon dioxide 35g;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture that step poly-(2) obtains is mixed homogeneously with metformin hydrochloride by equal increments method, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity, PLURONICS F87, PVPk30 to be dissolved in 60 DEG C of purified water and to stir; Adding repaglinide stirring after dissolving completely makes it dissolve completely:
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG
(11) bag gastric solubility film-coat, weightening finish about 3%;
(12) high-density polyethylene bottle packaging;
Every 10000 specification 500mg/1mg Repaglinide-metformin hydrochloride sheets contain:
The preparation method of the Repaglinide-metformin hydrochloride sheet described in the present embodiment, comprises following steps:
(1) metformin hydrochloride 5000g is taken, microcrystalline Cellulose 690g, sorbitol 100g, PVPk30 200g, polyvinylpolypyrrolidone 280g, repaglinide 10g, PLURONICS F87 40g, meglumine 20g, PVPk305g, silicon dioxide 35g;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture that step poly-(2) obtains is mixed homogeneously with metformin hydrochloride by equal increments method, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity, PLURONICS F87, PVPk30 to be dissolved in 60 DEG C of purified water and to stir; Adding repaglinide stirring after dissolving completely makes it dissolve completely:
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG
(11) bag gastric solubility film-coat, weightening finish about 3%; ;
(12) high-density polyethylene bottle packaging;
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (5)
1. Repaglinide-metformin hydrochloride sheet, is characterized in that, every 10000 Repaglinide-metformin hydrochloride sheets contain: 500mg/2mg specification
。
2. Repaglinide-metformin hydrochloride sheet, is characterized in that, every 10000 Repaglinide-metformin hydrochloride sheets contain: 500mg/1mg specification
。
3. a kind of compound Repaglinide-metformin hydrochloride sheet according to claim 1 and 2, is characterized in that, every 10000 specification 500mg/2mg compound Repaglinide-metformin hydrochloride sheets contain:
。
4. a kind of compound Repaglinide-metformin hydrochloride sheet according to claim 1 or 2 or 3, is characterized in that, every 10000 specification 500mg/1mg compound Repaglinide-metformin hydrochloride sheets contain:
。
5. the preparation process of claim 1 or 2 or the compound Repaglinide-metformin hydrochloride sheet described in 3 or 4, it is characterized in that, comprise the following steps:
(1) take above-mentioned substance by recipe quantity, described recipe quantity refers to material and content described in claim 1 or 2 or 3;
(2) by microcrystalline Cellulose, sorbitol, polyvinylpolypyrrolidone, PVPk30 crosses 80 eye mesh screens respectively, mix homogeneously;
(3) metformin hydrochloride is crossed 100 eye mesh screens, the mixture that step poly-(2) obtains is mixed homogeneously with metformin hydrochloride by equal increments method, drops in wet mixing pelletizer, stir 10 ~ 20 minutes;
(4) take Purified Water q. s, heating in water bath to 60 DEG C, respectively the meglumine of recipe quantity, PLURONICS F87, PVPk30 to be dissolved in 60 DEG C of purified water and to stir;
(5) solution of step poly-(4) is added in wet mixing pelletizer, stir 5 ~ 10 minutes, make soft material;
(6) 30 mesh sieve orders are crossed with oscillating granulator, obtained wet granular;
Drying 1.5 ~ 2 hours in (7) 55 ~ 65 DEG C of baking railway carriage or compartments, dried particles oscillating granulator 24 order granulate;
(8) silicon dioxide crosses 80 mesh sieves, and dry granule adds the silicon dioxide of recipe quantity, and three-dimensional mixer mixes 10 minutes;
(9) granule water content control is below 1%;
(10) special-shaped stamping, Hardness Control is at 10-12KG;
(11) bag gastric solubility film-coat, weightening finish about 3%;
(12) high-density polyethylene bottle packaging.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310336643.9A CN104337811A (en) | 2013-08-02 | 2013-08-02 | Repaglinide-metformin hydrochloride tablet and preparing method thereof |
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| CN201310336643.9A CN104337811A (en) | 2013-08-02 | 2013-08-02 | Repaglinide-metformin hydrochloride tablet and preparing method thereof |
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| CN104224783A (en) * | 2014-09-19 | 2014-12-24 | 四川海思科制药有限公司 | Medicine composition containing repaglinide and metformin and preparation method of medicine composition |
| CN106309444A (en) * | 2016-09-27 | 2017-01-11 | 山东明仁福瑞达制药股份有限公司 | Preparation method of composition of repaglinide and metformin hydrochloride |
| WO2017156953A1 (en) * | 2016-03-17 | 2017-09-21 | 赛乐医药科技(上海)有限公司 | Metformin hydrochloride osmotic pump tablet and preparation method therefor |
| CN109884201A (en) * | 2019-03-01 | 2019-06-14 | 山东省药学科学院 | Detector is combined the impurity of Repaglinide in method measurement Repaglinide diformin tablet |
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| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
| CN103070864A (en) * | 2012-12-06 | 2013-05-01 | 华润赛科药业有限责任公司 | Repaglinide and metformin hydrochloride medicinal composition and its preparation method |
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| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104224783A (en) * | 2014-09-19 | 2014-12-24 | 四川海思科制药有限公司 | Medicine composition containing repaglinide and metformin and preparation method of medicine composition |
| CN104224783B (en) * | 2014-09-19 | 2019-09-10 | 四川海思科制药有限公司 | A kind of pharmaceutical composition of the melbine containing Repaglinide and preparation method thereof |
| WO2017156953A1 (en) * | 2016-03-17 | 2017-09-21 | 赛乐医药科技(上海)有限公司 | Metformin hydrochloride osmotic pump tablet and preparation method therefor |
| US10668021B2 (en) | 2016-03-17 | 2020-06-02 | Elite Pharma Technology (Shanghai) Co., Ltd. | Metformin hydrochloride osmotic pump tablet and preparation method therefor |
| CN106309444A (en) * | 2016-09-27 | 2017-01-11 | 山东明仁福瑞达制药股份有限公司 | Preparation method of composition of repaglinide and metformin hydrochloride |
| CN109884201A (en) * | 2019-03-01 | 2019-06-14 | 山东省药学科学院 | Detector is combined the impurity of Repaglinide in method measurement Repaglinide diformin tablet |
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Application publication date: 20150211 |